Mapping functional circuits is a major goal for both cellular and systems neuroscience. Current approaches for mapping neural circuits are limited by the lack of technologies for evoking cell-specific neural activity. Available methods of neural stimulation rely on either local application of undiscriminating fields of electrical currents, glutamate uncaging, or the presentation of artificial sensory stimuli. Although recent use of light- gated ion channels has provided optical control of neuronal activity on rapid time scales, such approaches are limited by the requirement for direct optical access to neuronal populations of interest, and are not currently suitable for activating large brain areas or disperse neuronal populations. A transformative technology for neuroscience would be non-invasive control over neural activity in genetically defined populations of neurons in the mammalian brain. Such a goal requires combining genetic sensitization of neuronal subsets with a means to manipulate their electrical activity remotely without surgery or intracranial implants. To create such a technology, my laboratory has initiated a program of in vivo chemical genetic and physiological studies to engineer a mouse model suitable for precise non-invasive manipulation of neural activity in genetically defined populations of neurons in vivo. We have developed a conditional mouse model that sensitizes genetically defined neurons to an artificial ligand (capsaicin) by cell type-specific expression of a heterologous receptor (TRPV1). We have found that application of capsaicin to neurons expressing TRPV1 induces strong inward currents, triggers robust firing of action potentials, and activates stereotyped behaviors. Taking advantage of these preliminary data, and the extensive pharmacological and biophysical characterization of TRPV1, we propose to extend and modify this model to enable peripheral administration of agonists for central activation of defined neuronal subsets. Moreover, because the large TRPV1 channel pore is permeable to small molecules, including the membrane-impermeant sodium channel blocker QX-314, we propose to test this novel mouse model to enable both activation and inhibition of neuronal activity. This work will allow for the development of a novel in vivo technology for chemical genetic regulation of neuronal activity that is (1) orthogonal to optical and optogenetic strategies, (2) based on the only current Cre/lox-based model for neuronal activation, (3) may allow for fully non-invasive CNS activation by drug injection, and (4) may enable targeted small molecule delivery to defined neuronal subsets. PUBLIC HEALTH RELEVANCE: The proposed research will develop a novel technology for non-invasive control over electrical activity in genetically defined populations of brain cells. Abnormal electrical activity in the brain contributes to epilepsy, memory decline, depression, autism, schizophrenia, and addiction. By developing a crucial new technology for targeted manipulation of brain cell activity and metabolism, the proposed research will define novel brain circuits and therapeutic strategies for treating these devastating neurological and psychiatric disorders, which currently have a profound negative impact on public health.